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Exposure to engineered nanomaterials (ENM) poses a potential health risk to humans throughlong-term, repetitive low-dose exposures. Currently, this is not commonplace within in vitro lungcell cultures. Therefore, the purpose of this study was to consider the optimal exposureapproach toward determining the stability, sensitivity and validity of using in vitro lung cellmono- and co-cultures to determine ENM hazard. A range of exposure scenarios wereconducted with DQ12 (previously established as a positive particle control) (historic and reactivated),TiO2 (JRC NM–105) and BaSO4 (JRC NM–220) on both monocultures of A549 cells aswell as co-cultures of A549 cells anddifferentiated THP-1 cells. Cell cultures were exposed toeither a single, or a repeated exposure over 24, 48- or 72-hours at in vivo extrapolated concentrationsof 0–5.2 mg/cm2, 0-6mg/cm2 and 0-1mg/cm2. The focus of this study was the pro-inflammatory,cytotoxic and genotoxic response elicited by these ENMs. Exposure to DQ12 caused proinflammatoryresponses after 48 hours repeat exposures, as well as increases in micronucleus frequency.Neither TiO2 nor BaSO4 elicited a pro-inflammatory response at this time point.However, there was induction of IL-6 after 24 hours TiO2 exposure. In conclusion, it is importantto consider the appropriateness of the positive control implemented, the cell culture model, thetime of exposure as well as the type of exposure (bolus or fractionated) before establishing if anin vitro model is appropriate to determine the level of response to the specific ENM of interest.

Background Toxicity assessment for regulatory purposes is starting to move away from traditional in vivo methods and towards new approach methodologies (NAM) such as high-throughput in vitro models and computational tools. For materials with limited hazard information, utilising quantitative Adverse Outcome Pathways (AOPs) in a testing strategy involving NAM can produce information relevant for risk assessment. The aim of this work was to determine the feasibility of linking in vitro endpoints to in vivo events, and moreover to key events associated with the onset of a chosen adverse outcome to aid in the development of NAM testing strategies. To do this, we focussed on the adverse outcome pathway (AOP) relating to the onset of pulmonary fibrosis. Results We extracted in vivo and in vitro dose–response information for particles known to induce this pulmonary fibrosis (crystalline silica, specifically α-quartz). To test the in vivo–in vitro extrapolation (IVIVE) determined for crystalline silica, cerium dioxide nanoparticles (nano-CeO2) were used as a case study allowing us to evaluate our findings with a less studied substance. The IVIVE methodology outlined in this paper is formed of five steps, which can be more generally summarised into two categories (i) aligning the in vivo and in vitro dosimetry, (ii) comparing the dose–response curves and derivation of conversion factors. Conclusion Our analysis shows promising results with regards to correlation of in vitro cytokine secretion to in vivo acute pulmonary inflammation assessed by polymorphonuclear leukocyte influx, most notable is the potential of using IL-6 and IL-1β cytokine secretion from simple in vitro submerged models as a screening tool to assess the likelihood of lung inflammation at an early stage in product development, hence allowing a more targeted investigation using either a smaller, more targeted in vivo study or in the future a more complex in vitro protocol. This paper also highlights the strengths and limitations as well as the current difficulties in performing IVIVE assessment and suggestions for overcoming these issues.

Additional file1. Literature screening methodology, graphical comparisons of in vivo and in vitro responses, and data analysis results. Figure S1. IL-8, IL-6, IL-1β and TNF-α cytokine responses in vitro compared to PMN influx in vivo following exposure to α-quartz. Figure S2. IL-8, IL-6, IL-1β and TNF-α cytokine responses in vitro compared to PMN influx in vivo following exposure to nano-CeO2. Table S1. Data analysis results for in vitro studies. Table S2. Data analysis results for in vivo studies. Table S3. CIs for various BMR applied in BMD analysis. Table S4 Model comparisons for α-quartz using log-log regression analysis. Table S5. Model comparisons for nano-CeO2 using log-log regression analysis.

The aim of this study is to investigate the impact of foreign exchange reserves accumulation on the investment of companies in Vietnam. A detailed data of 332 firms listed on Hochiminh Stock Exchange is collected over the period from the first quarter of 2009 to the first quarter of 2019. Generalized Method of Moments (GMM) is employed to test the proposed hypotheses in this study. Estimation results reveal that great changes in foreign exchange reserves reduce corporate investment. Besides that, according to the growth stage of reserve accumulation, to some extent, foreign exchange reserve accumulation benefits domestic investment. However, when reserves increases tremendously, it may cause negative effect to investment. The study also investigates the impact of foreign exchange reserves on investment of companies in different industries. Empirical findings point out that for firms which are newly listed, young, small, and has low investment in fixed asset and low dividend payout ratio, the investment-cash flow sensitivity is very high. Changing in foreign exchange reserves does not greatly affect firm investment. In contrast, for enterprises which are long-established, large, and has high fixed asset value and high dividend payout ratio, the investment-cash flow sensitivity is lower. However, large change in the accumulation of reserves adversely affects firm investment. The empirical findings imply that government should be more cautious in managing foreign exchange reserves and firms should develop a plan to effectively manage their cash in order to lower borrowing costs as well as to less depend on external financing sources.

ENPRA was one of the earlier multidisciplinary European Commission FP7-funded projects aiming to evaluate the risks associated with nanomaterial (NM) exposure on human health across pulmonary, cardiovascular, hepatic, renal, and developmental systems. The outputs from this project have formed the basis of this review. A retrospective interpretation of the findings across a wide range of in vitro and in vivo studies was performed to identify the main highlights from the project. In particular, focus was placed on informing what advances were made in the hazard assessment of NM, as well as offering some suggestions on the future of "nanotoxicology research" based on these observations, shortcomings, and lessons learned from the project. A number of issues related to the hazard assessment of NM are discussed in detail and include use of appropriate NM for nanotoxicology investigations; characterization and dispersion of NM; use of appropriate doses for all related investigations; need for the correct choice of experimental models for risk assessment purposes; and full understanding of the test systems and correct interpretation of data generated from in vitro and in vivo systems. It is hoped that this review may assist in providing information in the implementation of guidelines, model systems, validation of assessment methodology, and integrated testing approaches for risk assessment of NM. It is vital to learn from ongoing and/or completed studies to avoid unnecessary duplication and offer suggestions that might improve different aspects of experimental design.

The world's population is steadily ageing and as a result, health conditions related to ageing, such as dementia, have become a major public health concern. In 2001, it was estimated that there were almost 5 million Europeans suffering from Alzheimer's disease (AD) and this figure has been projected to almost double by 2040. About 40% of people over 85 suffer from AD, and another 10% from Parkinson's disease (PD). The majority of AD and PD cases are of sporadic origin and environmental factors play an important role in the aetiology. Epidemiological research identified airborne particulate matter (PM) as one of the environmental factors potentially involved in AD and PD pathogenesis. Also, cumulating evidence demonstrates that the smallest sizes of the inhalable fraction of ambient particulate matter, also referred to as ultrafine particulate matter or nano-sized particles, are capable of inducing effects beyond the respiratory system. Translocation of very small particles via the olfactory epithelium in the nose or via uptake into the circulation has been demonstrated through experimental rodent studies with engineered nanoparticles. Outdoor air pollution has been linked to several health effects including oxidative stress and neuroinflammation that may ultimately result in neurodegeneration and cognitive impairment. This review aims to evaluate the relationship between exposure to inhaled ambient particles and neurodegeneration.

This file contains the NCBI taxonomy versions used in the experiments, the experimental results to validate the impact of parameters on the classification performance of SeMeta, and the effect of the usage of cluster cores on SeMeta. (PDF 423 kb)

This file contains the details of the simulated datasets used in this study, and the experimental results of SeMeta on a sample of Human Gut Metagenome. (PDF 90 kb)

The EU H2020 BIORIMA project is one of the first and largest European initiatives that is totally dedicated to the development of innovative and robust methodologies to assess and manage the risks of nano-biomaterials (NBM) that are used in medical devices and advanced medicinal therapy products, along their whole life cycle, and at the same time identify and implement suitable safety-by-design alternatives. The BIORIMA consortium is implementing a comprehensive method testing and validation program to adapt and further develop existing tools for human and environmental exposure and hazard assessment of NBM, beyond clinical studies. All approaches that are tested and developed are integrated into a risk management framework (RMF) to help practitioners and end-users in finding best practical solutions for testing and handling of NBM. The RMF will be implemented by means of a web-based and specially designed Decision Support System (DSS), to comply with existing relevant regulations, such as MDR 2017/745 or REACH. The poster describes the latest findings of the project after 3 years of intensive research on the hazard of NBM and of the underlying mechanisms that are crucial for the effects and exposure we observe in humans and the environment.

Titania (TiO2) nanoparticles were surface modified using silica and citrate to implement a ‘safe-by-design' approach for managing potential toxicity of titania nanoparticles by controlling surface redox reactivity. DLS and zeta-potential analyses confirmed the surface modification, and electron microscopy and surface area measurements demonstrated nanoscale dimensions of the particles. Electron paramagnetic resonance (EPR) was used to determine the exogenous generation of reactive oxygen species (ROS). All the produced spray dried nanotitania lowered levels of ROS when compared to the corresponding dispersed nanotitania, suggesting that the spray drying process is an appropriate design strategy for the control of nano TiO2 ROS reactivity. The modification of nanotitania with silica and with citrate resulted in increased levels of ROS generation in exogenous measurements, including photoexcitation for 60 minutes. The dichlorodihydrofluorescein (DCFH) assay of dose-dependent production of oxidative stress, generated by pristine and modified nanotitania in macrophages and alveolar epithelial cells, found no significant change in toxicity originating from the generation of reactive oxygen species. Our findings show that there is no direct correlation between the photocatalytic activity of nanotitania and its oxidative stress-mediated potential toxicity, and it is possible to improve the former, for example adding silica as a modifying agent, without altering the cell redox equilibrium.